Inhibitors of IRAK4 activity

ABSTRACT

The present invention relates to inhibitors of IRAK4 of Formula (I) and provides compositions comprising such inhibitors, as well as methods therewith for treating IRAK4-mediated or -associated conditions or diseases.

BACKGROUND OF THE INVENTION

The present invention is directed to compounds which modulateinterleukin-1 (IL-1) receptor-associated kinase 4 (IRAK4) and are usefulin the prevention or treatment of inflammatory, cell proliferative andimmune-related conditions and diseases.

The recruitment of immune cells to sites of injury involves theconcerted interactions of a large number of soluble mediators. Severalcytokines appear to play key roles in these processes, particularly IL-1and TNF. Both cytokines are derived from mononuclear cells andmacrophages, along with other cell types. Physiologically, they producemany of the same proinflammatory responses, including fever, sleep andanorexia, mobilization and activation of polymorphonuclear leukocytes,induction of cyclooxygenase and lipoxygenase enzymes, increase inadhesion molecule expression, activation of B-cells, T-cells and naturalkiller cells, and stimulation of production of other cytokines. Otheractions include a contribution to the tissue degeneration observed inchronic inflammatory conditions, such as stimulation of fibroblastproliferation, induction of collagenase, etc. They have also beenimplicated in the process of bone resorption and adipose tissueregulation. Thus, these cytokines play key roles in a large number ofpathological conditions, including rheumatoid arthritis, inflammatorybowel disease, multiple sclerosis, diabetes, obesity, cancer, sepsis,etc.

The importance of IL-1 in inflammation has been demonstrated by theability of the highly specific IL-1 receptor antagonist protein (IL-1Raor IRAP) to relieve inflammatory conditions. See, e.g., Dinarello,Cytokine Growth Factor Rev., 1997, 8:253-265.

IL-1 treatment of cells induces the formation of a complex consisting ofthe two IL-1 receptor chains, IL-1R1 and IL-1RAcP, and the resultingheterodimer recruits an adaptor molecule designated as MyD88. See e.g.,Wesche et al., J. Biol. Chem., 1999, 274:19403-19410. MyD88 binds to aprotein designated IRAK (IL-1 receptor associated kinase). See, e.g.,O'Neill et al., J. Leukoc. Biol., 1998, 63(6):650-657; Auron, CytokineGrowth Factor Rev., 1998, 9(3-4):221-237; and O'Neill, Biochem. Soc.Trans., 2000, 28(5):557-563. IRAK is subsequently phosphorylated andreleased from the receptor complex to interact with a tumor necrosisfactor receptor-associated factor, TRAF6, which transduces the signal todownstream effector molecules. See e.g., Cao et al., Nature, 1996,383:443-446. TRAF6 can trigger the NIK/IKK kinase cascade to activatethe transcription factor NK-kappa B. NF-kappa B regulates a number ofgenes that, in turn, regulate immune and inflammatory responses.

Four IRAKs have been identified: IRAK1 (see, e.g., Cao et al., Science,1996, 271:1128-1131), IRAK2 (see, e.g. Muzio et al., Science, 1997,278:1612-1615), the monomyeloic cell specific IRAKM, also known as IRAK3(see, e.g., Wesche et al., J. Biol. Chem., 1999, 274:19403-19410), andIRAK4 (see, e.g., PCT Publication No. WO 01/051641). IRAK proteins havebeen shown to play a role in transducing signals other than thoseoriginating from IL-1 receptors, including signals triggered byactivation of IL-18 receptors (see, e.g., Kanakaraj et al., J. Exp.Med., 1999, 189(7):1129-1138) and LPS receptors (see, e.g., Yang et al.,J. Immunol., 1999, 163:639-643; and Wesche et al., J. Biol. Chem., 1999,274:19403-19410). Over-expression of IRAK2 and IRAKM has been shown tobe capable of reconstituting the response to IL-1 and LPS in an IRAKdeficient cell line.

The identification of compounds that inhibit the function of IRAK4represents an attractive approach to the development of therapeuticagents for the treatment of inflammatory, cell proliferative andimmune-related conditions and diseases associated with IRAK4-mediatedsignal transduction, such as rheumatoid arthritis, inflammatory boweldisease, multiple sclerosis, diabetes, obesity, allergic disease,psoriasis, asthma, graft rejection, cancer, and sepsis.

It is an object of the instant invention to provide novel compounds thatare inhibitors of IRAK4.

It is also an object of the present invention to provide pharmaceuticalcompositions that comprise the novel compounds that are inhibitors ofIRAK4.

It is also an object of the present invention to provide a method fortreating IRAK4-mediated and associated conditions or diseases thatcomprises administering such inhibitors of IRAK4 activity.

SUMMARY OF THE INVENTION

The present invention relates to inhibitors of IRAK4 of formula (1) andprovides compositions comprising such inhibitors, as well as methodstherewith for treating IRAK4-mediated or associated conditions ordiseases.

DETAILED DESCRIPTION OF THE INVENTION

The compounds of the instant invention are useful in the inhibition ofthe activity of IRAK4.

An embodiment of the instant invention is illustrated by the Formula I:

wherein:

X is CH or N;

a is 0 or 1; b is 0 or 1; m is 0, 1 or 2;

Ring A is (C₃-C₈)cycloalkyl, (C₃-C₈)cycloalkenyl, aryl or heterocycleoptionally substituted with one to three substituents independentlyselected from R₁;

R₁ is selected from: H, oxo, (C═O)_(a)O_(b)(C₁-C₁₀)alkyl,(C═O)_(a)O_(b)-aryl, (C═O)_(a)O_(b)(C₂-C₁₀)alkenyl,(C═O)_(a)O_(b)(C₂-C₁₀)alkynyl, CO₂H, halo, OH, O_(b)(C₁-C₆)fluoroalkyl,(C═O)_(a)NR₅R₆, CN, (C═O)_(a)O_(b)(C₃-C₈)cycloalkyl, S(O)_(m)NR₅R₆, SH,S(O)_(m)-(C₁-C₁₀)alkyl and (C═O)_(a)O_(b)-heterocyclyl, said alkyl,aryl, alkenyl, alkynyl, cycloalkyl, and heterocyclyl are optionallysubstituted with one or more substituents selected from R_(a);

R₂ and R₃ are independently selected from: H, (C═O)_(a)O_(b)C₁-C₁₀alkyl, (C═O)_(a)O_(b)aryl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl,(C═O)_(a)O_(b) heterocyclyl, CO₂H, CN, O_(b)C₁-C₆ fluoroalkyl,O_(a)(C═O)_(b)NR₅R₆, CHO, (N═O)R₅R₆, S(O)_(m)NR₅R₆, SH,S(O)_(m)—(C₁-C₁₀)alkyl, (C═O)_(a)O_(b)C₃-C₈ cycloalkyl, optionallysubstituted with one or more substituents selected from R₁; or R₂ and R₃can be taken together with the nitrogen to which they are attached toform a monocyclic or bicyclic heterocycle with 3-7 members in each ringand optionally containing, in addition to the nitrogen, one or twoadditional heteroatoms selected from N, O and S, said monocyclic orbicyclic heterocycle optionally substituted with one or moresubstituents selected from R₁;

R₄ is selected from: (C₁-C₆)alkyl and (C₃-C₆)cycloalkyl, optionallysubstituted with R_(a);

R₅ and R₆ are independently selected from: H, oxo,(C═O)_(a)O_(b)(C₁-C₁₀)alkyl, (C═O)_(a)O_(b)-aryl,(C═O)_(a)O_(b)(C₂-C₁₀)alkenyl, (C═O)_(a)O_(b)(C₂-C₁₀)alkynyl, CO₂H,O_(b)(C₁-C₆)fluoroalkyl, (C═O)_(a)N(R_(a))₂, CN,(C═O)_(a)O_(b)(C₃-C₈)cycloalkyl, S(O)_(m) N(R_(a))₂, SH,S(O)_(m)—(C₁-C₁₀)alkyl and (C═O)_(a)O_(b)-heterocyclyl, said alkyl,aryl, alkenyl, alkynyl, cycloalkyl, and heterocyclyl are optionallysubstituted with one or more substituents selected from R_(a);

R_(a) is independently selected from R_(b), OH, (C₁-C₆)alkoxy, halogen,cyclopropyl, CO₂H, CN, O_(a)(C═O)_(b)(C₁-C₆)alkyl, oxo, and N(R_(b))₂;and

R_(b) is independently selected from H and (C₁-C₆)alkyl;

or a pharmaceutically acceptable salt or a stereoisomer thereof.

Another embodiment of the instant invention is illustrated by theFormula II:

wherein:

X is CH or N;

a is 0 or 1; b is 0 or 1; m is 0, 1 or 2;

Ring A is selected from phenyl and heterocyclyl optionally substitutedwith one to three substituents independently selected from R₁;

R₁ is selected from: H, oxo, (C═O)_(a)O_(b)(C₁-C₁₀)alkyl,(C═O)_(a)O_(b)-aryl, (C═O)_(a)O_(b)(C₂-C₁₀)alkenyl,(C═O)_(a)O_(b)(C₂-C₁₀)alkynyl, CO₂H, halo, OH,O_(b)(C₁-C₆)perfluoroalkyl, (C═O)_(a)NR₅R₆, CN,(C═O)_(a)O_(b)(C₃-C₈)cycloalkyl, S(O)_(m)NR₅R₆, SH,S(O)_(m)—(C₁-C₁₀)alkyl and (C═O)_(a)O_(b)-heterocyclyl, said alkyl,aryl, alkenyl, alkynyl, cycloalkyl, and heterocyclyl are optionallysubstituted with one or more substituents selected from R_(a);

R₄ is selected from: (C₁-C₄)alkyl optionally substituted with OH,methoxy and halogen;

R₅ and R₆ are independently selected from: H,(C═O)_(a)O_(b)(C₁-C₁₀)alkyl, (C═O)_(a)O_(b)-aryl,(C═O)_(a)O_(b)(C₂-C₁₀)alkenyl, (C═O)_(a)O_(b)(C₂-C₁₀)alkynyl, CO₂H,O_(b)(C₁-C₆)fluoroalkyl, (C═O)_(a)N(R_(a))₂, CN,(C═O)_(a)O_(b)(C₃-C₈)cycloalkyl, S(O)_(m) N(R_(a))₂, SH,S(O)_(m)—(C₁-C₁₀)alkyl and (C═O)_(a)O_(b)-heterocyclyl, said alkyl,aryl, alkenyl, alkynyl, cycloalkyl, and heterocyclyl are optionallysubstituted with one or more substituents selected from R_(a);

R_(a) is independently selected from R_(b), OH, (C₁-C₆)alkoxy, halogen,cyclopropyl, CO₂H, CN, O_(a)(C═O)_(b)(C₁-C₆)alkyl, oxo, and N(R_(b))₂;and

R_(b) is independently selected from H and (C₁-C₆)alkyl;

or a pharmaceutically acceptable salt or a stereoisomer thereof.

Another embodiment of the instant invention is illustrated by theFormula III:

wherein:

X is CH or N;

a is 0 or 1; b is 0 or 1; m is 0, 1 or 2;

R₁ is selected from: H, oxo, (C═O)_(a)O_(b)(C₁-C₁₀)alkyl,(C═O)_(a)O_(b)-aryl, (C═O)_(a)O_(b)(C₂-C₁₀)alkenyl,(C═O)_(a)O_(b)(C₂-C₁₀)alkynyl, CO₂H, halo, OH,O_(b)(C₁-C₆)perfluoroalkyl, (C═O)_(a)NR₅R₆, CN,(C═O)_(a)O_(b)(C₃-C₈)cycloalkyl, S(O)_(m)NR₅R₆, SH,S(O)_(m)—(C₁-C₁₀)alkyl and (C═O)_(a)O_(b)-heterocyclyl, said alkyl,aryl, alkenyl, alkynyl, cycloalkyl, and heterocyclyl are optionallysubstituted with one or more substituents selected from R_(a);

R₅ and R₆ are independently selected from: H,(C═O)_(a)O_(b)(C₁-C₁₀)alkyl, (C═O)_(a)O_(b)-aryl,(C═O)_(a)O_(b)(C₂-C₁₀)alkenyl, (C═O)_(a)O_(b)(C₂-C₁₀)alkynyl, CO₂H,O_(b)(C₁-C₆)perfluoroalkyl, (C═O)_(a)N(R_(a))₂, CN,(C═O)_(a)O_(b)(C₃-C₈)cycloalkyl, S(O)_(m) N(R_(a))₂, SH,S(O)_(m)—(C₁-C₁₀)alkyl and (C═O)_(a)O_(b)-heterocyclyl, said alkyl,aryl, alkenyl, alkynyl, cycloalkyl, and heterocyclyl are optionallysubstituted with one or more substituents selected from R_(a);

R_(a) is independently selected from R_(b), OH, (C₁-C₆)alkoxy, halogen,cyclopropyl, CO₂H, CN, O_(a)(C═O)_(b)(C₁-C₆)alkyl, oxo, and N(R_(b))₂;and

R_(b) is independently selected from H and (C₁-C₆)alkyl;

or a pharmaceutically acceptable salt or a stereoisomer thereof.

A compound of the instant invention is selected from:

-   N-(3-carbamoyl-1-methyl-1H-pyrazol-4-yl)-2′-((cyclopropylmethyl)amino)-[2,4′-bipyridine]-6-carboxamide    (1);-   N-(3-carbamoyl-1-methyl-1H-pyrazol-4-yl)-6-(1H-pyrrol-1-yl)picolinamide    (2);-   4-(3-(2-(cyclopropylmethylamino)pyridin-4-yl)benzamido)-1-methyl-1H-pyrazole-3-carboxamide    (3);-   tert-butyl(6-((3-carbamoyl-1-methyl-1H-pyrazol-4-yl)carbamoyl)-[2,4′-bipyridin]-2′-yl)carbamate    (4);-   N-(3-carbamoyl-1-methyl-1H-pyrazol-4-yl)-2′-(cyclopropylmethylamino)-2,4′-bipyridine-4-carboxamide    (5);-   2′-amino-N-(3-carbamoyl-1-methyl-1H-pyrazol-4-yl)-[2,4′-bipyridine]-6-carboxamide    (6);-   N-(3-carbamoyl-1-methyl-1H-pyrazol-4-yl)-2′-(cyclopropylmethylamino)-3,4′-bipyridine-5-carboxamide    (7);-   N-(5-carbamoyl-1-methyl-1H-pyrazol-4-yl)-2′-(cyclopropylmethylamino)-2,4′-bipyridine-6-carboxamide    (8);-   N-(3-carbamoyl-1-methyl-1H-pyrazol-4-yl)-6-morpholinopicolinamide    (9);-   N-(3-carbamoyl-1-methyl-1H-pyrazol-4-yl)-6-(piperazin-1-yl)picolinamide    (10);-   N-(3-carbamoyl-1-methyl-1H-pyrazol-4-yl)-2,4′-bipyridine-6-carboxamide    (11);-   N-(3-carbamoyl-1-methyl-1H-pyrazol-4-yl)-[2,3′-bipyridine]-6-carboxamide    (12);-   N-(3-carbamoyl-1-methyl-1H-pyrazol-4-yl)-6-(3-methoxyphenyl)picolinamide    (13);-   N-(3-carbamoyl-1-methyl-1H-pyrazol-4-yl)-6-phenylpicolinamide (14);-   N-(3-carbamoyl-1-methyl-1H-pyrazol-4-yl)-2′-((2-methoxyethyl)amino)-[2,4′-bipyridine]-6-carboxamide    (15);-   N-(3-carbamoyl-1-methyl-1H-pyrazol-4-yl)-2′-((2,2-difluoroethyl)amino)-[2,4′-bipyridine]-6-carboxamide    (16);-   N-(3-carbamoyl-1-methyl-1H-pyrazol-4-yl)-2′-(((tetrahydro-2H-pyran-4-yl)methyl)amino)-[2,4′-bipyridine]-6-carboxamide    (17);-   N-(3-carbamoyl-1-methyl-1H-pyrazol-4-yl)-2′-((2,2,2-trifluoroethyl)amino)-[2,4′-bipyridine]-6-carboxamide    (18);-   N-(3-carbamoyl-1-methyl-1H-pyrazol-4-yl)-2-(2-((cyclopropylmethyl)amino)pyridin-4-yl)pyrimidine-4-carboxamide    (19);-   N-(3-carbamoyl-1-methyl-1H-pyrazol-4-yl)-2′-methoxy-[2,3′-bipyridine]-6-carboxamide    (20);-   N-(3-carbamoyl-1-methyl-1H-pyrazol-4-yl)-6-(3-(trifluoromethoxy)phenyl)picolinamide    (21);-   N-(3-carbamoyl-1-methyl-1H-pyrazol-4-yl)-6-(thiophen-3-yl)picolinamide    (22);-   N-(3-carbamoyl-1-methyl-1H-pyrazol-4-yl)-6′-morpholino-[2,3′-bipyridine]-6-carboxamide    (23);-   N-(3-carbamoyl-1-methyl-1H-pyrazol-4-yl)-6-(3-(methylcarbamoyl)phenyl)picolinamide    (24);-   N-(3-carbamoyl-1-methyl-1H-pyrazol-4-yl)-6-(1-methyl-1H-pyrazol-4-yl)picolinamide    (25);-   N-(3-carbamoyl-1-methyl-1H-pyrazol-4-yl)-6-(1,1-dioxido-3,6-dihydro-2H-thiopyran-4-yl)picolinamide    (26);-   N-(3-carbamoyl-1-methyl-1H-pyrazol-4-yl)-6-(5,6-dihydro-2H-pyran-3-yl)picolinamide    (27);-   N-(3-carbamoyl-1-methyl-1H-pyrazol-4-yl)-6′-cyclopropyl-[2,3′-bipyridine]-6-carboxamide    (28);-   N-(3-carbamoyl-1-methyl-1H-pyrazol-4-yl)-5′-chloro-[2,3′-bipyridine]-6-carboxamide    (29);-   N-(3-carbamoyl-1-methyl-1H-pyrazol-4-yl)-6-(3,6-dihydro-2H-pyran-4-yl)picolinamide    (30);-   N-(3-carbamoyl-1-methyl-1H-pyrazol-4-yl)-4′-chloro-[2,3′-bipyridine]-6-carboxamide    (31);-   N-(3-carbamoyl-1-methyl-1H-pyrazol-4-yl)-1′-methyl-6′-oxo-1′,2′,3′,6′-tetrahydro-[2,4′-bipyridine]-6-carboxamide    (32);-   N-(3-carbamoyl-1-methyl-1H-pyrazol-4-yl)-1′-methyl-1′,2′,5′,6′-tetrahydro-[2,3′-bipyridine]-6-carboxamide    (33);-   2′-((cyclopropylmethyl)amino)-N-(1-methyl-3-(((1-methylpyrrolidin-3-yl)methyl)carbamoyl)-1H-pyrazol-4-yl)-[2,4′-bipyridine]-6-carboxamide    (34);-   2′-((cyclopropylmethyl)amino)-N-(1-methyl-3-((2-(pyrrolidin-1-yl)ethyl)carbamoyl)-1H-pyrazol-4-yl)-[2,4′-bipyridine]-6-carboxamide    (35);-   N-(3-(((1H-imidazol-2-yl)methyl)carbamoyl)-1-methyl-1H-pyrazol-4-yl)-2′-((cyclopropylmethyl)amino)-[2,4′-bipyridine]-6-carboxamide    (36);-   2′-((cyclopropylmethyl)amino)-N-(3-((5-(dimethylamino)pentyl)carbamoyl)-1-methyl-1H-pyrazol-4-yl)-[2,4′-bipyridine]-6-carboxamide    (37);-   2′-((cyclopropylmethyl)amino)-N-(1-methyl-3-((2-(pyridin-2-yl)ethyl)carbamoyl)-1H-pyrazol-4-yl)-[2,4′-bipyridine]-6-carboxamide    (38);-   2′-((cyclopropylmethyl)amino)-N-(1-methyl-3-(4-methylpiperazine-1-carbonyl)-1H-pyrazol-4-yl)-[2,4′-bipyridine]-6-carboxamide    (39);-   2′-((cyclopropylmethyl)amino)-N-(3-((3-(dimethylamino)propyl)carbamoyl)-1-methyl-1H-pyrazol-4-yl)-[2,4′-bipyridine]-6-carboxamide    (40);-   2′-((cyclopropylmethyl)amino)-N-(1-methyl-3-(morpholine-4-carbonyl)-1H-pyrazol-4-yl)-[2,4′-bipyridine]-6-carboxamide    (41);-   N-(3-(3-(aminomethyl)azetidine-1-carbonyl)-1-methyl-1H-pyrazol-4-yl)-2′-((cyclopropylmethyl)amino)-[2,4′-bipyridine]-6-carboxamide    (42);-   2′-((cyclopropylmethyl)amino)-N-(1-methyl-3-(pyrimidin-5-ylcarbamoyl)-1H-pyrazol-4-yl)-[2,4′-bipyridine]-6-carboxamide    (43);-   2′-((cyclopropylmethyl)amino)-N-(1-methyl-3-((2-(pyrazin-2-yl)ethyl)carbamoyl)-1H-pyrazol-4-yl)-[2,4′-bipyridine]-6-carboxamide    (44);-   2′-((cyclopropylmethyl)amino)-N-(3-(((1,1-dioxidotetrahydrothiophen-3-yl)methyl)carbamoyl)-1-methyl-1H-pyrazol-4-yl)-[2,4′-bipyridine]-6-carboxamide    (45);-   2′-((cyclopropylmethyl)amino)-N-(3-((3S,4S)-3-(dimethylamino)-4-hydroxypyrrolidine-1-carbonyl)-1-methyl-1H-pyrazol-4-yl)-[2,4′-bipyridine]-6-carboxamide    (46);-   2′-((cyclopropylmethyl)amino)-N-(1-methyl-3-((pyrimidin-4-ylmethyl)carbamoyl)-1H-pyrazol-4-yl)-[2,4′-bipyridine]-6-carboxamide    (47);-   N-(3-(((1,3,4-thiadiazol-2-yl)methyl)carbamoyl)-1-methyl-1H-pyrazol-4-yl)-2′-((cyclopropylmethyl)amino)-[2,4′-bipyridine]-6-carboxamide    (48);-   2′-((cyclopropylmethyl)amino)-N-(1-methyl-3-(((1-methylpiperidin-3-yl)methyl)carbamoyl)-1H-pyrazol-4-yl)-[2,4′-bipyridine]-6-carboxamide    (49);-   N-(3-((2-(1H-pyrazol-1-yl)ethyl)carbamoyl)-1-methyl-1H-pyrazol-4-yl)-2′-((cyclopropylmethyl)amino)-[2,4′-bipyridine]-6-carboxamide    (50); and-   2′-((cyclopropylmethyl)amino)-N-(1-methyl-3-((tetrahydrofuran-3-yl)carbamoyl)-1H-pyrazol-4-yl)-[2,4′-bipyridine]-6-carboxamide    (51);-   or a pharmaceutically acceptable salt or stereoisomer thereof

A compound of the instant invention is selected from:

-   N-(3-carbamoyl-1-methyl-1H-pyrazol-4-yl)-2′-((cyclopropylmethyl)amino)-[2,4′-bipyridine]-6-carboxamide    (1);-   N-(3-carbamoyl-1-methyl-1H-pyrazol-4-yl)-[2,3′-bipyridine]-6-carboxamide    (12);-   N-(3-carbamoyl-1-methyl-1H-pyrazol-4-yl)-2′-((2-methoxyethyl)amino)-[2,4′-bipyridine]-6-carboxamide    (15);-   N-(3-carbamoyl-1-methyl-1H-pyrazol-4-yl)-2′-((2,2-difluoroethyl)amino)-[2,4′-bipyridine]-6-carboxamide    (16);-   N-(3-carbamoyl-1-methyl-1H-pyrazol-4-yl)-2′-((2,2,2-trifluoroethyl)amino)-[2,4′-bipyridine]-6-carboxamide    (18);-   N-(3-carbamoyl-1-methyl-1H-pyrazol-4-yl)-6-(thiophen-3-yl)picolinamide    (22);-   N-(3-carbamoyl-1-methyl-1H-pyrazol-4-yl)-6′-cyclopropyl-[2,3′-bipyridine]-6-carboxamide    (28);-   N-(3-carbamoyl-1-methyl-1H-pyrazol-4-yl)-1′-methyl-6′-oxo-1′,2′,3′,6′-tetrahydro-[2,4′-bipyridine]-6-carboxamide    (32);-   N-(3-(3-(aminomethyl)azetidine-1-carbonyl)-1-methyl-1H-pyrazol-4-yl)-2′-((cyclopropylmethyl)amino)-[2,4′-bipyridine]-6-carboxamide    (42); and-   2′-((cyclopropylmethyl)amino)-N-(1-methyl-3-(((1-methylpiperidin-3-yl)methyl)carbamoyl)-1H-pyrazol-4-yl)-[2,4′-bipyridine]-6-carboxamide    (49);-   or a pharmaceutically acceptable salt or stereoisomer thereof.

The compounds of the present invention may have asymmetric centers,chiral axes, and chiral planes (as described in: E. L. Eliel and S. H.Wilen, Stereochemistry of Carbon Compounds, John Wiley & Sons, New York,1994, pages 1119-1190), and occur as racemates, racemic mixtures, and asindividual diastereomers, with all possible isomers and mixturesthereof, including optical isomers, all such stereoisomers beingincluded in the present invention.

In addition, the compounds disclosed herein may exist as tautomers andboth tautomeric forms are intended to be encompassed by the scope of theinvention, even though only one tautomeric structure is depicted.

This invention is also intended to encompass pro-drugs of the compoundsdisclosed herein. A prodrug of any of the compounds can be made usingwell known pharmacological techniques.

When any variable (e.g. R₁, etc.) occurs more than one time in anyconstituent, its definition on each occurrence is independent at everyother occurrence. Also, combinations of substituents and variables arepermissible only if such combinations result in stable compounds. Linesdrawn into the ring systems from substituents represent that theindicated bond may be attached to any of the substitutable ring atoms.If the ring system is bicyclic, it is intended that the bond be attachedto any of the suitable atoms on either ring of the bicyclic moiety.

In the compounds of Formulas I-III, the atoms may exhibit their naturalisotopic abundances, or one or more of the atoms may be artificiallyenriched in a particular isotope having the same atomic number, but anatomic mass or mass number different from the atomic mass or mass numberpredominantly found in nature. The present invention is meant to includeall suitable isotopic variations of the compounds of Formulas I-III. Forexample, different isotopic forms of hydrogen (H) include protium (¹H)and deuterium (²H). Protium is the predominant hydrogen isotope found innature. Enriching for deuterium may afford certain therapeuticadvantages, such as increasing in vivo half-life or reducing dosagerequirements, or may provide a compound useful as a standard forcharacterization of biological samples. Isotopically-enriched compoundswithin Formulas I-III can be prepared without undue experimentation byconventional techniques well known to those skilled in the art or byprocesses analogous to those described in the Scheme and Examples hereinusing appropriate isotopically-enriched reagents and/or intermediates.

It is understood that one or more silicon (Si) atoms can be incorporatedinto the compounds of the instant invention in place of one or morecarbon atoms by one of ordinary skill in the art to provide compoundsthat are chemically stable and that can be readily synthesized bytechniques known in the art from readily available starting materials.Carbon and silicon differ in their covalent radius leading todifferences in bond distance and the steric arrangement when comparinganalogous C-element and Si-element bonds. These differences lead tosubtle changes in the size and shape of silicon-containing compoundswhen compared to carbon. One of ordinary skill in the art wouldunderstand that size and shape differences can lead to subtle ordramatic changes in potency, solubility, lack of off target activity,packaging properties, and so on. (Diass, J. O. et al. Organometallics(2006) 5:1188-1198; Showell, G. A. et al. Bioorganic & MedicinalChemistry Letters (2006) 16:2555-2558).

It is understood that substituents and substitution patterns on thecompounds of the instant invention can be selected by one of ordinaryskill in the art to provide compounds that are chemically stable andthat can be readily synthesized by techniques known in the art, as wellas those methods set forth below, from readily available startingmaterials. If a substituent is itself substituted with more than onegroup, it is understood that these multiple groups may be on the samecarbon or on different carbons, so long as a stable structure results.The phrase “optionally substituted with one or more substituents” shouldbe taken to be equivalent to the phrase “optionally substituted with atleast one substituent” and in such cases the preferred embodiment willhave from zero to four substituents, and the more preferred embodimentwill have from zero to three substituents.

As used herein, “alkyl” is intended to include both branched andstraight-chain saturated aliphatic hydrocarbon groups having thespecified number of carbon atoms. For example, C₁-C₁₀, as in“(C₁-C₁₀)alkyl” is defined to include groups having 1, 2, 3, 4, 5, 6, 7,8, 9 or 10 carbons in a linear or branched arrangement. For example,“(C₁-C₁₀)alkyl” specifically includes methyl, ethyl, n-propyl, i-propyl,n-butyl, t-butyl, i-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl,and so on.

The term “cycloalkyl” means a monocyclic saturated aliphatic hydrocarbongroup having the specified number of carbon atoms. For example, C₃-C₈,as in “(C₃-C₈)cycloalkyl” is defined to include groups having 3, 4, 5,6, 7 or 8 carbons which includes a circular arrangement.

For example, “(C₃-C₈)cycloalkyl” includes cyclopropyl,methyl-cyclopropyl, 2,2-dimethyl-cyclobutyl, 2-ethyl-cyclopentyl,cyclohexyl, and so on.

“Alkoxy” represents either a cyclic or non-cyclic alkyl group ofindicated number of carbon atoms attached through an oxygen bridge.“Alkoxy” therefore encompasses the definitions of alkyl and cycloalkylabove.

If no number of carbon atoms is specified, the term “alkenyl” refers toa non-aromatic hydrocarbon radical, straight, branched or cyclic,containing from 2 to 10 carbon atoms and at least one carbon to carbondouble bond. Preferably one carbon to carbon double bond is present, andup to four non-aromatic carbon-carbon double bonds may be present. Thus,“(C₂-C₁₀)alkenyl” means an alkenyl radical having from 2 to 10 carbonatoms. Alkenyl groups include ethenyl, propenyl, butenyl,2-methylbutenyl and cyclohexenyl. The straight, branched or cyclicportion of the alkenyl group may contain double bonds and may besubstituted if a substituted alkenyl group is indicated.

The term “alkynyl” refers to a hydrocarbon radical straight, branched orcyclic, containing from 2 to 10 carbon atoms and at least one carbon tocarbon triple bond. Up to three carbon-carbon triple bonds may bepresent. Thus, “(C₂-C₁₀)alkynyl” means an alkynyl radical having from 2to 10 carbon atoms. Alkynyl groups include ethynyl, propynyl, butynyl,3-methylbutynyl and so on. The straight, branched or cyclic portion ofthe alkynyl group may contain triple bonds and may be substituted if asubstituted alkynyl group is indicated.

As used herein, “aryl” is intended to mean any stable monocyclic orbicyclic carbon ring of up to 7 atoms in each ring, wherein at least onering is aromatic. Examples of such aryl elements include phenyl,naphthyl, tetrahydro-naphthyl, indanyl and biphenyl. In cases where thearyl substituent is bicyclic and one ring is non-aromatic, it isunderstood that attachment is via the aromatic ring. In one embodimentof Formulas I-III, aryl is independently selected from phenyl, naphthyl,tetrahydro-naphthyl, indanyl and biphenyl optionally substituted withone to three substituents independently selected from R_(a). In anotherembodiment of Formulas I-III, aryl is independently selected fromphenyl, naphthyl, tetrahydro-naphthyl, indanyl and biphenyl.

The term “heterocycle” or “heterocyclyl” as used herein is intended tomean a 3- to 10-membered aromatic or nonaromatic heterocycle containingfrom 1 to 4 heteroatoms selected from the group consisting of O, N andS, and includes bicyclic groups. “Heterocyclyl” therefore includesheteroaryls, as well as dihydro and tetrathydro analogs thereof. Furtherexamples of “heterocyclyl” include, but are not limited to thefollowing: benzoimidazolyl, benzoimidazolonyl, benzofuranyl,benzofurazanyl, benzopyrazolyl, benzotriazolyl, benzothiophenyl,benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, furanyl, imidazolyl,indolinyl, indolyl, indolazinyl, indazolyl, isobenzofuranyl, isoindolyl,isoquinolyl, isothiazolyl, isoxazolyl, naphthpyridinyl, oxadiazolyl,oxazolyl, oxazoline, isoxazoline, oxetanyl, pyranyl, pyrazinyl,pyrazolyl, pyridazinyl, pyridopyridinyl, pyridazinyl, pyridyl,pyrimidyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl,tetrahydropyranyl, tetrazolyl, tetrazolopyridyl, thiadiazolyl,thiazolyl, thienyl, triazolyl, azetidinyl, 1,4-dioxanyl,hexahydroazepinyl, piperazinyl, piperidinyl, pyridin-2-onyl,pyrrolidinyl, morpholinyl, thiomorpholinyl, dihydrobenzoimidazolyl,dihydrobenzofuranyl, dihydrobenzothiophenyl, dihydrobenzoxazolyl,dihydrofuranyl, dihydroimidazolyl, dihydroindolyl, dihydroisooxazolyl,dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl,dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl,dihydropyrimidinyl, dihydropyrrolyl, dihydroquinolinyl,dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl,dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl,methylenedioxybenzoyl, tetrahydrofuranyl, and tetrahydrothienyl, andN-oxides thereof. Attachment of a heterocyclyl substituent can occur viaa carbon atom or via a heteroatom.

In one embodiment of Formulas I-III, heterocyclyl is independentlyselected from benzoimidazolyl, benzoimidazolonyl, benzofuranyl,benzofurazanyl, benzopyrazolyl, benzotriazolyl, benzothiophenyl,benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, furanyl, imidazolyl,indolinyl, indolyl, indolazinyl, indazolyl, isobenzofuranyl, isoindolyl,isoquinolyl, isothiazolyl, isoxazolyl, naphthpyridinyl, oxadiazolyl,oxazolyl, oxazoline, isoxazoline, oxetanyl, pyranyl, pyrazinyl,pyrazolyl, pyridazinyl, pyridopyridinyl, pyridazinyl, pyridyl,pyrimidyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl,tetrahydropyranyl, tetrazolyl, tetrazolopyridyl, thiadiazolyl,thiazolyl, thienyl, triazolyl, azetidinyl, 1,4-dioxanyl,hexahydroazepinyl, piperazinyl, piperidinyl, pyridin-2-onyl,pyrrolidinyl, morpholinyl, thiomorpholinyl, dihydrobenzoimidazolyl,dihydrobenzofuranyl, dihydrobenzothiophenyl, dihydrobenzoxazolyl,dihydrofuranyl, dihydroimidazolyl, dihydroindolyl, dihydroisooxazolyl,dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl,dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl,dihydropyrimidinyl, dihydropyrrolyl, dihydroquinolinyl,dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl,dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl,methylenedioxybenzoyl, tetrahydrofuranyl, and tetrahydrothienyl, andN-oxides thereof, optionally substituted with one to three substituentsindependently selected from R_(a).

In another embodiment of Formulas I-III, heterocyclyl is independentlyselected from benzoimidazolyl, benzoimidazolonyl, benzofuranyl,benzofurazanyl, benzopyrazolyl, benzotriazolyl, benzothiophenyl,benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, furanyl, imidazolyl,indolinyl, indolyl, indolazinyl, indazolyl, isobenzofuranyl, isoindolyl,isoquinolyl, isothiazolyl, isoxazolyl, naphthpyridinyl, oxadiazolyl,oxazolyl, oxazoline, isoxazoline, oxetanyl, pyranyl, pyrazinyl,pyrazolyl, pyridazinyl, pyridopyridinyl, pyridazinyl, pyridyl,pyrimidyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl,tetrahydropyranyl, tetrazolyl, tetrazolopyridyl, thiadiazolyl,thiazolyl, thienyl, triazolyl, azetidinyl, 1,4-dioxanyl,hexahydroazepinyl, piperazinyl, piperidinyl, pyridin-2-onyl,pyrrolidinyl, morpholinyl and thiomorpholinyl.

In another embodiment of Formulas I-III, heterocyclyl is independentlyselected from carbazolyl, carbolinyl, cinnolinyl, furanyl, imidazolyl,indolinyl, indolyl, indolazinyl, indazolyl, isobenzofuranyl, isoindolyl,isoquinolyl, isothiazolyl, isoxazolyl, naphthpyridinyl, oxadiazolyl,oxazolyl, oxazoline, isoxazoline, oxetanyl, pyranyl, pyrazinyl,pyrazolyl, pyridazinyl, pyridopyridinyl, pyridazinyl, pyridyl,pyrimidyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl,tetrahydropyranyl, tetrazolyl, tetrazolopyridyl, thiadiazolyl,thiazolyl, thienyl, triazolyl, azetidinyl, 1,4-dioxanyl,hexahydroazepinyl, piperazinyl, piperidinyl, pyridin-2-onyl,pyrrolidinyl, morpholinyl and thiomorpholinyl.

As appreciated by those of skill in the art, “halo” or “halogen” as usedherein is intended to include chloro (Cl), fluoro (F), bromo (Br) andiodo (I).

In an embodiment of Formula I and II, Ring A is aryl, heteroaryl orheterocycle optionally substituted with one to three substituentsindependently selected from R₁.

In another embodiment of Formula I and II, Ring A is phenyl,benzoimidazolyl, benzoimidazolonyl, benzofuranyl, benzofurazanyl,benzopyrazolyl, benzotriazolyl, benzothiophenyl, benzoxazolyl,carbazolyl, carbolinyl, cinnolinyl, furanyl, imidazolyl, indolinyl,indolyl, indolazinyl, indazolyl, isobenzofuranyl, isoindolyl,isoquinolyl, isothiazolyl, isoxazolyl, naphthpyridinyl, oxadiazolyl,oxazolyl, oxazoline, isoxazoline, oxetanyl, pyranyl, pyrazinyl,pyrazolyl, pyridazinyl, pyridopyridinyl, pyridazinyl, pyridyl,pyrimidyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl,tetrahydropyranyl, tetrazolyl, tetrazolopyridyl, thiadiazolyl,thiazolyl, thienyl, triazolyl, azetidinyl, 1,4-dioxanyl,hexahydroazepinyl, piperazinyl, piperidinyl, pyridin-2-onyl,pyrrolidinyl, morpholinyl and thiomorpholinyl, which are optionallysubstituted with one to three substituents independently selected fromR₁.

In another embodiment of Formula I and II, Ring A is phenyl, pyrazinyl,pyrazolyl, pyridyl, pyrimidyl, thienyl, piperazinylfuranyl,pyrrolozinyl, pyrrolidinyl, oxazolyl, thiazolyl, imidazolyl, isozazolyl,oxadiazolyl, triazolyl, thiadiazolyl, piperidinyl, pyridazinyl. andmorpholinyl, which are optionally substituted with one to threesubstituents independently selected from R₁.

In another embodiment of Formula I and II, Ring A is phenyl, pyrazinyl,pyrazolyl, pyridyl, pyrimidyl, thienyl, piperazinyl, furanyl,pyrrolozinyl, pyrrolidinyl, oxazolyl, thiazolyl, imidazolyl, isozazolyl,oxadiazolyl, triazolyl, thiadiazolyl, piperidinyl, pyridazinyl.

and morpholinyl, which are optionally substituted with one to threesubstituents independently selected from R_(a).

In another embodiment of Formula I and II, Ring A is phenyl, pyrazinyl,pyrazolyl, pyridyl, pyrimidyl, thienyl, piperazinylfuranyl,pyrrolozinyl, pyrrolidinyl, oxazolyl, thiazolyl, imidazolyl, isozazolyl,oxadiazolyl, triazolyl, thiadiazolyl, piperidinyl, pyridazinyl. andmorpholinyl, which are optionally substituted with one to threesubstituents independently selected from R_(b).

In an embodiment of Formula I, II and III, R₁ is independently selectedfrom: H, oxo, (C═O)_(a)(C₁-C₁₀)alkyl, (C═O)_(a)-aryl, CO₂H, halo, OH,O_(b)(C₁-C₆)fluoroalkyl, (C═O)_(a)NR₅R₆, CN, (C═O)_(a)(C₃-C₈)cycloalkyland (C═O)_(a)O_(b)-heterocyclyl, said alkyl, aryl, cycloalkyl, andheterocyclyl are optionally substituted with one or more substituentsselected from R_(a).

In another embodiment of Formula I, II and III, R₁ is independentlyselected from: H, oxo, (C₁-C₆)alkyl, aryl, CO₂H, halo, OH,(C₁-C₆)fluoroalkyl, NR₅R₆, CN, (C₃-C₈)cycloalkyl and heterocyclyl, saidalkyl, aryl, cycloalkyl, and heterocyclyl are optionally substitutedwith one to three substituents selected from R_(a).

In another embodiment of Formula I, II and III, R₁ is independentlyselected from: H and NR₅R₆.

In another embodiment of Formula I, II and III, R₁ is independentlyselected from: H and N(R_(a))₂.

In another embodiment of Formula I, II and III, R₁ is independentlyselected from: H and N(R_(b))₂.

In another embodiment of Formula I, II and III, R₁ is:

In another embodiment of Formula I, II and III, R₁ is H.

In an embodiment of Formula I, R₂ and R₃ are independently selectedfrom: H and C₁-C₆ alkyl, optionally substituted with one or moresubstituents selected from R₁; or R₂ and R₃ can be taken together withthe nitrogen to which they are attached to form a monocyclic heterocyclewith 3-7 members in each ring and optionally containing, in addition tothe nitrogen, one or two additional heteroatoms selected from N, O andS, said monocyclic or bicyclic heterocycle optionally substituted withone or more substituents selected from R₁.

In another embodiment of Formula I, R₂ and R₃ are independently selectedfrom: H and C₁-C₆ alkyl, optionally substituted with one to threesubstituents selected from R_(a); or R₂ and R₃ can be taken togetherwith the nitrogen to which they are attached to form a monocyclicheterocycle with 3-7 members in each ring and optionally containing, inaddition to the nitrogen, one or two additional heteroatoms selectedfrom N, O and S, said monocyclic or bicyclic heterocycle optionallysubstituted with one to three substituents selected from R_(a).

In another embodiment of Formula I, R₂ and R₃ are independently selectedfrom: H and C₁-C₆ alkyl, optionally substituted with one to threesubstituents selected from R_(b); or R₂ and R₃ can be taken togetherwith the nitrogen to which they are attached to form a monocyclicheterocycle with 3-7 members in each ring and optionally containing, inaddition to the nitrogen, one or two additional heteroatoms selectedfrom N, O and S, said monocyclic or bicyclic heterocycle optionallysubstituted with one to three substituents selected from R_(b).

In an embodiment of Formula I and II, R₄ is selected from (C₁-C₆)alkyloptionally substituted with OH, methoxy and halogen.

In another embodiment of Formula I and II, R₄ is selected from(C₁-C₄)alkyl.

In another embodiment of Formula I and II, R₄ is methyl.

In an embodiment of Formula I, II and III, R₅ and R₆ are independentlyselected from: H, (C═O)_(a)(C₁-C₁₀)alkyl, (C═O)_(a)(C₃-C₈)cycloalkyl,(C═O)_(a)-aryl, (C═O)_(a)-heterocyclyl and (C═O)_(a)NR_(a2).

In another embodiment of Formula I, II and III, R₅ and R₆ areindependently selected from: H, (C═O)_(a)(C₁-C₆)alkyl,(C═O)_(a)(C₃-C₆)cycloalkyl, (C═O)_(a)-phenyl, (C═O)_(a)-heterocyclyl and(C═O)_(a)NR_(a2).

In another embodiment of Formula I, II and III, R₅ and R₆ areindependently selected from: H, (C═O)_(a)(C₁-C₄)alkyl,(C═O)_(a)(C₃)cycloalkyl, (C═O)_(a)-phenyl, and (C═O)_(a)NR_(b2).

In an embodiment of Formula I, II and III, R_(a) is independentlyselected from R_(b), OH, (C₁-C₆)alkoxy, halogen, cyclopropyl, CO₂H, CN,O_(a)(C═O)_(b)(C₁-C₆)alkyl, oxo, and N(R_(b))₂.

In another embodiment of Formula I, II and III, R_(a) is independentlyselected from R_(b), OH, (C₁-C₄)alkoxy, halogen, cyclopropyl, CO₂H, CN,(C₁-C₄)alkyl, oxo, and N(R_(b))₂.

In another embodiment of Formula I, II and III, R_(a) is independentlyselected from R_(b), (C₁-C₆)alkoxy, cyclopropyl, CO₂H, CN,O_(a)(C═O)_(b)(C₁-C₆)alkyl, and N(R_(b))₂.

In an embodiment of Formula I, II and III, R_(b) is independentlyselected from H and methyl.

Included in the instant invention is the free form of compounds ofFormulas I-III, as well as the pharmaceutically acceptable salts andstereoisomers thereof. Some of the isolated specific compoundsexemplified herein are the protonated salts of amine compounds. The term“free form” refers to the amine compounds in non-salt form. Theencompassed pharmaceutically acceptable salts not only include theisolated salts exemplified for the specific compounds described herein,but also all the typical pharmaceutically acceptable salts of the freeform of compounds of Formulas I-III. The free form of the specific saltcompounds described may be isolated using techniques known in the art.For example, the free form may be regenerated by treating the salt witha suitable dilute aqueous base solution such as dilute aqueous NaOH,potassium carbonate, ammonia and sodium bicarbonate. The free forms maydiffer from their respective salt forms somewhat in certain physicalproperties, such as solubility in polar solvents, but the acid and basesalts are otherwise pharmaceutically equivalent to their respective freeforms for purposes of the invention.

The pharmaceutically acceptable salts of the instant compounds can besynthesized from the compounds of this invention which contain a basicor acidic moiety by conventional chemical methods. Generally, the saltsof the basic compounds are prepared either by ion exchangechromatography or by reacting the free base with stoichiometric amountsor with an excess of the desired salt-forming inorganic or organic acidin a suitable solvent or various combinations of solvents. Similarly,the salts of the acidic compounds are formed by reactions with theappropriate inorganic or organic base.

Thus, pharmaceutically acceptable salts of the compounds of thisinvention include the conventional non-toxic salts of the compounds ofthis invention as formed by reacting a basic instant compound with aninorganic or organic acid. For example, conventional non-toxic saltsinclude those derived from inorganic acids such as hydrochloric,hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like, aswell as salts prepared from organic acids such as acetic, propionic,succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic,pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic,salicylic, sulfanilic, 2-acetoxy-benzoic, fumaric, toluenesulfonic,methanesulfonic, ethane disulfonic, oxalic, isethionic, trifluoroacetic(TFA) and the like.

When the compound of the present invention is acidic, suitable“pharmaceutically acceptable salts” refers to salts prepared formpharmaceutically acceptable non-toxic bases including inorganic basesand organic bases. Salts derived from inorganic bases include aluminum,ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganicsalts, manganous, potassium, sodium, zinc and the like. Particularlypreferred are the ammonium, calcium, magnesium, potassium and sodiumsalts. Salts derived from pharmaceutically acceptable organic non-toxicbases include salts of primary, secondary and tertiary amines,substituted amines including naturally occurring substituted amines,cyclic amines and basic ion exchange resins, such as arginine, betainecaffeine, choline, N,N′-dibenzylethylenediamine, diethylamin,2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine,ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine,glucosamine, histidine, hydrabamine, isopropylamine, lysine,methylglucamine, morpholine, piperazine, piperidine, polyamine resins,procaine, purines, theobromine, triethylamine, trimethylaminetripropylamine, tromethamine and the like.

The preparation of the pharmaceutically acceptable salts described aboveand other typical pharmaceutically acceptable salts is more fullydescribed by Berg et al., “Pharmaceutical Salts,” J. Pharm. Sci.,1977:66:1-19.

It will also be noted that the compounds of the present invention arepotentially internal salts or zwitterions, since under physiologicalconditions a deprotonated acidic moiety in the compound, such as acarboxyl group, may be anionic, and this electronic charge might then bebalanced off internally against the cationic charge of a protonated oralkylated basic moiety, such as a quaternary nitrogen atom.

UTILITY

According to yet another embodiment, the present invention provides amethod of treating or reducing the severity of a disease in a patient byusing a compound of Formulas I-III as described above, wherein saiddisease is selected from IRAK4 mediated pathologies, such as rheumatoidarthritis, multiple sclerosis, sepsis, osteoarthritis, inflammatorybowel disease, Parkinson's disease, cardiac contractile dysfunction,type I diabetes, type II diabetes or familial cold autoinflammatorysyndrome, allergic disease, cancer, psoriasis, asthma or graftrejection.

The compounds of the invention find use in a variety of applications. Aswill be appreciated by those skilled in the art, the kinase activity ofIRAK-4 may be modulated in a variety of ways; that is, one can affectthe phosphorylation/activation of IRAK-4 either by modulating theinitial phosphorylation of the protein or by modulating theautophosphorylation of the other active sites of the protein.Alternatively, the kinase activity of IRAK-4 may be modulated byaffecting the binding of a substrate of IRAK-4 phosphorylation.

The compounds of the invention are used to treat or prevent inflammationrelated diseases. Disease states which can be treated by the methods andcompositions provided herein include, but are not limited to, cancer,autoimmune disease, viral disease, fungal disease,neurological/neurodegenerative disorders, arthritis, inflammation,anti-proliferative (e.g. ocular retinopathy), neuronal, alopecia,cardiovascular disease, graft rejection, inflammatory bowel disease,proliferation induced after medical procedures, including, but notlimited to, surgery, angioplasty, and the like. It is appreciated thatin some cases the cells may not be in a hyper- or hypoproliferationstate (abnormal state) and still require treatment. Thus, in oneembodiment, the invention herein includes application to cells orindividuals which are afflicted or may eventually become afflicted withany one of these disorders or states.

The compounds of this invention may be administered to mammals,including humans, either alone or, in combination with pharmaceuticallyacceptable carriers, excipients or diluents, in a pharmaceuticalcomposition, according to standard pharmaceutical practice. Thecompounds can be administered orally or parenterally, including theintravenous, intramuscular, intraperitoneal, subcutaneous and topicalroutes of administration.

The pharmaceutical compositions containing the active ingredient may bein a form suitable for oral use, for example, as tablets, troches,lozenges, aqueous or oily suspensions, dispersible powders or granules,emulsions, hard or soft capsules, or syrups or elixirs. Compositionsintended for oral use may be prepared according to any method known tothe art for the manufacture of pharmaceutical compositions and suchcompositions may contain one or more agents selected from the groupconsisting of sweetening agents, flavoring agents, coloring agents andpreserving agents in order to provide pharmaceutically elegant andpalatable preparations. Tablets contain the active ingredient inadmixture with non-toxic pharmaceutically acceptable excipients whichare suitable for the manufacture of tablets. These excipients may be forexample, inert diluents, such as calcium carbonate, sodium carbonate,lactose, calcium phosphate or sodium phosphate; granulating anddisintegrating agents, for example, microcrystalline cellulose, sodiumcrosscarmellose, corn starch, or alginic acid; binding agents, forexample starch, gelatin, polyvinyl-pyrrolidone or acacia, andlubricating agents, for example, magnesium stearate, stearic acid ortalc. The tablets may be uncoated or they may be coated by knowntechniques to mask the unpleasant taste of the drug or delaydisintegration and absorption in the gastrointestinal tract and therebyprovide a sustained action over a longer period. For example, a watersoluble taste masking material such as hydroxypropylmethyl-cellulose orhydroxypropylcellulose, or a time delay material such as ethylcellulose, cellulose acetate buryrate may be employed.

Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules wherein the active ingredient is mixed with watersoluble carrier such as polyethyleneglycol or an oil medium, for examplepeanut oil, liquid paraffin, or olive oil.

Aqueous suspensions contain the active material in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydroxypropylmethyl-cellulose,sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatide,for example lecithin, or condensation products of an alkylene oxide withfatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethylene-oxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more preservatives, forexample ethyl, or n-propyl p-hydroxybenzoate, one or more coloringagents, one or more flavoring agents, and one or more sweetening agents,such as sucrose, saccharin or aspartame.

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil, for example arachis oil, olive oil, sesame oil orcoconut oil, or in mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set forthabove, and flavoring agents may be added to provide a palatable oralpreparation. These compositions may be preserved by the addition of ananti-oxidant such as butylated hydroxyanisol or alpha-tocopherol.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients, for example sweetening, flavoring and coloringagents, may also be present. These compositions may be preserved by theaddition of an anti-oxidant such as ascorbic acid.

The pharmaceutical compositions of the invention may also be in the formof an oil-in-water emulsion. The oily phase may be a vegetable oil, forexample olive oil or arachis oil, or a mineral oil, for example liquidparaffin or mixtures of these. Suitable emulsifying agents may benaturally-occurring phosphatides, for example soy bean lecithin, andesters or partial esters derived from fatty acids and hexitolanhydrides, for example sorbitan monooleate, and condensation productsof the said partial esters with ethylene oxide, for examplepolyoxyethylene sorbitan monooleate. The emulsions may also containsweetening, flavouring agents, preservatives and antioxidants.

Syrups and elixirs may be formulated with sweetening agents, for exampleglycerol, propylene glycol, sorbitol or sucrose. Such formulations mayalso contain a demulcent, a preservative, flavoring and coloring agentsand antioxidant.

The pharmaceutical compositions may be in the form of sterile injectableaqueous solutions. Among the acceptable vehicles and solvents that maybe employed are water, Ringer's solution and isotonic sodium chloridesolution.

The sterile injectable preparation may also be a sterile injectableoil-in-water microemulsion where the active ingredient is dissolved inthe oily phase. For example, the active ingredient may be firstdissolved in a mixture of soybean oil and lecithin. The oil solutionthen introduced into a water and glycerol mixture and processed to forma microemulation.

The injectable solutions or microemulsions may be introduced into apatient's blood-stream by local bolus injection. Alternatively, it maybe advantageous to administer the solution or microemulsion in such away as to maintain a constant circulating concentration of the instantcompound. In order to maintain such a constant concentration, acontinuous intravenous delivery device may be utilized. An example ofsuch a device is the Deltec CADD-PLUS™ model 5400 intravenous pump.

The pharmaceutical compositions may be in the form of a sterileinjectable aqueous or oleagenous suspension for intramuscular andsubcutaneous administration. This suspension may be formulated accordingto the known art using those suitable dispersing or wetting agents andsuspending agents which have been mentioned above. The sterileinjectable preparation may also be a sterile injectable solution orsuspension in a non-toxic parenterally-acceptable diluent or solvent,for example as a solution in 1,3-butane diol. In addition, sterile,fixed oils are conventionally employed as a solvent or suspendingmedium. For this purpose any bland fixed oil may be employed includingsynthetic mono- or diglycerides. In addition, fatty acids such as oleicacid find use in the preparation of injectables.

For topical use, creams, ointments, jellies, solutions or suspensions,etc., containing the compound of Formulas I-III are employed. (Forpurposes of this application, topical application shall include mouthwashes and gargles.)

The compounds for the present invention can be administered inintranasal form via topical use of suitable intranasal vehicles anddelivery devices, or via transdermal routes, using those forms oftransdermal skin patches well known to those of ordinary skill in theart. To be administered in the form of a transdermal delivery system,the dosage administration will, of course, be continuous rather thanintermittent throughout the dosage regimen. Compounds of the presentinvention may also be delivered as a suppository employing bases such ascocoa butter, glycerinated gelatin, hydrogenated vegetable oils,mixtures of polyethylene glycols of various molecular weights and fattyacid esters of polyethylene glycol.

When a composition according to this invention is administered into ahuman subject, the daily dosage will normally be determined by theprescribing physician with the dosage generally varying according to theage, weight, and response of the individual patient, as well as theseverity of the patient's symptoms.

The dosage regimen utilizing the compounds of the instant invention canbe selected in accordance with a variety of factors including type, age,weight, sex; the route of administration; the renal and hepatic functionof the patient; and the particular compound or salt thereof employed. Anordinarily skilled physician or veterinarian can readily determine andprescribe the effective amount of the drug required to treat, forexample, to prevent, inhibit (fully or partially) or arrest the progressof the disease. For example, compounds of the instant invention can beadministered in a total daily dose of up to 10,000 mg. Compounds of theinstant invention can be administered once daily (QD), or divided intomultiple daily doses such as twice daily (BID), and three times daily(TID). Compounds of the instant invention can be administered at a totaldaily dosage of up to 10,000 mg, e.g., 2,000 mg, 3,000 mg, 4,000 mg,6,000 mg, 8,000 mg or 10,000 mg, which can be administered in one dailydose or can be divided into multiple daily doses as described above.

For example, compounds of the instant invention can be administered in atotal daily dose of up to 1,000 mg. Compounds of the instant inventioncan be administered once daily (QD), or divided into multiple dailydoses such as twice daily (BID), and three times daily (TID). Compoundsof the instant invention can be administered at a total daily dosage ofup to 1,000 mg, e.g., 200 mg, 300 mg, 400 mg, 600 mg, 800 mg or 1,000mg, which can be administered in one daily dose or can be divided intomultiple daily doses as described above.

In addition, the administration can be continuous, i.e., every day, orintermittently. The terms “intermittent” or “intermittently” as usedherein means stopping and starting at either regular or irregularintervals. For example, intermittent administration of a compound of theinstant invention may be administration one to six days per week or itmay mean administration in cycles (e.g. daily administration for two toeight consecutive weeks, then a rest period with no administration forup to one week) or it may mean administration on alternate days.

In addition, the compounds of the instant invention may be administeredaccording to any of the schedules described above, consecutively for afew weeks, followed by a rest period. For example, the compounds of theinstant invention may be administered according to any one of theschedules described above from two to eight weeks, followed by a restperiod of one week, or twice daily at a dose of 100-500 mg for three tofive days a week. In another particular embodiment, the compounds of theinstant invention may be administered three times daily for twoconsecutive weeks, followed by one week of rest.

Any one or more of the specific dosages and dosage schedules of thecompounds of the instant invention, may also be applicable to any one ormore of the therapeutic agents to be used in the combination treatment(hereinafter refered to as the “second therapeutic agent”).

Moreover, the specific dosage and dosage schedule of this secondtherapeutic agent can further vary, and the optimal dose, dosingschedule and route of administration will be determined based upon thespecific second therapeutic agent that is being used.

Of course, the route of administration of the compounds of the instantinvention is independent of the route of administration of the secondtherapeutic agent. In an embodiment, the administration for a compoundof the instant invention is oral administration. In another embodiment,the administration for a compound of the instant invention isintravenous administration. Thus, in accordance with these embodiments,a compound of the instant invention is administered orally orintravenously, and the second therapeutic agent can be administeredorally, parenterally, intraperitoneally, intravenously, intraarterially,transdermally, sublingually, intramuscularly, rectally, transbuccally,intranasally, liposomally, via inhalation, vaginally, intraoccularly,via local delivery by catheter or stent, subcutaneously,intraadiposally, intraarticularly, intrathecally, or in a slow releasedosage form.

In addition, a compound of the instant invention and second therapeuticagent may be administered by the same mode of administration, i.e. bothagents administered e.g. orally, by IV. However, it is also within thescope of the present invention to administer a compound of the instantinvention by one mode of administration, e.g. oral, and to administerthe second therapeutic agent by another mode of administration, e.g. IVor any other ones of the administration modes described hereinabove.

The first treatment procedure, administration of a compound of theinstant invention, can take place prior to the second treatmentprocedure, i.e., the second therapeutic agent, after the treatment withthe second therapeutic agent, at the same time as the treatment with thesecond therapeutic agent, or a combination thereof. For example, a totaltreatment period can be decided for a compound of the instant invention.The second therapeutic agent can be administered prior to onset oftreatment with a compound of the instant invention or followingtreatment with a compound of the instant invention.

The instant compounds are also useful in combination with othertherapeutic agents. Combinations of the presently disclosed compoundswith therapeutic agents are within the scope of the invention. A personof ordinary skill in the art would be able to discern which combinationsof agents would be useful based on the particular characteristics of thedrugs and the pathologies involved. The instant compounds are alsouseful in combination with known therapeutic agents.

The instant compounds are useful in combination with a knownanti-inflammatory agent. In one embodiment, the anti-inflammatory agentis a nonsteroidal anti-inflammatory drug (NSAID). In one embodiment, theNSAID is selected from the group consisting of salicylates,indomethacin, flurbiprofen, diclofenac, ketorolac, naproxen, piroxicam,tebufelone, ibuprofen, etodolac, nabumetone, tenidap, alcofenac,antipyrine, aminopyrine, dipyrone, aminopyrone, phenylbutazone,clofezone, oxyphenbutazone, prenazone, apazone, benzydamine, bucolome,cinchophen, clonixin, ditrazol, epirizole, fenoprofen, floctafenin,flufenamic acid, glaphenine, indoprofen, ketoprofen, loxoprofen,meclofenamic acid, mefenamic acid, niflumic acid, phenacetin,salidifamides, sulindac, suprofen, tolmetin, a pharmaceuticallyacceptable salt thereof, and a mixture thereof.

In another embodiment, the NSAID is a selective COX-2 inhibitor. Forpurposes of this specification NSAID's which are selective inhibitors ofCOX-2 are defined as those which possess a specificity for inhibitingCOX-2 over COX-1 of at least 100 fold as measured by the ratio of IC₅₀for COX-2 over IC₅₀ for COX-1 evaluated by cell or microsomal assays.Such compounds include, but are not limited to those disclosed in U.S.Pat. Nos. 5,474,995, 5,861,419, 6,001,843, 6,020,343, 5,409,944,5,436,265, 5,536,752, 5,550,142, 5,604,260, 5,698,584, 5,710,140, WO94/15932, U.S. Pat. Nos. 5,344,991, 5,134,142, 5,380,738, 5,393,790,5,466,823, 5,633,272, and 5,932,598, all of which are herebyincorporated by reference.

Compounds that have been described as specific inhibitors of COX-2 andare therefore useful in the present invention include, but are notlimited to: parecoxib, CELEBREX® and BEXTRA® or a pharmaceuticallyacceptable salt thereof.

The instant compounds are useful in combination with a known anti-canceragent. Combinations of the presently disclosed compounds withanti-cancer agents are within the scope of the invention. Examples ofsuch anti-cancer agents can be found in Cancer Principles and Practiceof Oncology by V. T. Devita and S. Hellman (editors), 6^(th) edition(Feb. 15, 2001), Lippincott Williams & Wilkins Publishers. A person ofordinary skill in the art would be able to discern which combinations ofagents would be useful based on the particular characteristics of thedrugs and the cancer involved. Such agents include the following:estrogen receptor modulators, androgen receptor modulators, retinoidreceptor modulators, cytotoxic/cytostatic agents, antiproliferativeagents, prenyl-protein transferase inhibitors, HMG-CoA reductaseinhibitors and other angiogenesis inhibitors, HIV protease inhibitors,reverse transcriptase inhibitors, inhibitors of cell proliferation andsurvival signaling, bisphosphonates, aromatase inhibitors, siRNAtherapeutics, γ-secretase inhibitors, agents that interfere withreceptor tyrosine kinases (RTKs) and agents that interfere with cellcycle checkpoints.

In one embodiment, the anti-cancer agent is selected from the groupconsisting of abarelix (Plenaxis depot®); aldesleukin (Prokine®);Aldesleukin (Proleukin®); Alemtuzumabb (Campath®); alitretinoin(Panretin®); allopurinol (Zyloprim®); altretamine (Hexalen®); amifostine(Ethyol®); anastrozole (Arimidex®); arsenic trioxide (Trisenox®);asparaginase (Elspar®); azacitidine (Vidaza®); bevacuzimab (Avastin®);bexarotene capsules (Targretin®); bexarotene gel (Targretin®); bleomycin(Blenoxane®); bortezomib (Velcade®); busulfan intravenous (Busulfex®);busulfan oral (Myleran®); calusterone (Methosarb®); capecitabine(Xeloda®); carboplatin (Paraplatin ®); carmustine (BCNU®, BiCNU®);carmustine (Gliadel®); carmustine with Polifeprosan 20 Implant (GliadelWafer®); celecoxib (Celebrex®); cetuximab (Erbitux®); chlorambucil(Leukeran®); cisplatin (Platinol®); cladribine (Leustatin®, 2-CdA®);clofarabine (Clolar®); cyclophosphamide (Cytoxan®, Neosar®);cyclophosphamide (Cytoxan Injection ®); cyclophosphamide (CytoxanTable®); cytarabine (Cytosar-U®); cytarabine liposomal (DepoCyt®);dacarbazine (DTIC-Dome®); dactinomycin, actinomycin D (Cosmegen®);Darbepoetin alfa (Aranesp®); daunorubicin liposomal (DanuoXome®);daunorubicin, daunomycin (Daunorubicin®); daunorubicin, daunomycin(Cerubidine®); Denileukin diftitox (Ontak®); dexrazoxane (Zinecard®);docetaxel (Taxotere®); doxorubicin (Adriamycin PFS®); doxorubicin(Adriamycin®, Rubex®); doxorubicin (Adriamycin PFS Injection®);doxorubicin liposomal (Doxil®); dromostanolone propionate(dromostanolone®); dromostanolone propionate (masterone injection®);Elliott's B Solution (Elliott's B Solution®); epirubicin (Ellence®);Epoetin alfa (epogen®); erlotinib (Tarceva®); estramustine (Emcyt®);etoposide phosphate (Etopophos®); etoposide, VP-16 (Vepeside®);exemestane (Aromasin®); Filgrastim (Neupogen®); floxuridine(intraarterial) (FUDR®); fludarabine (Fludara®); fluorouracil, 5-FU(Adrucil®); fulvestrant (Faslodex®); gefitinib (Iressa®); gemcitabine(Gemzar®); gemtuzumab ozogamicin (Mylotarg®); goserelin acetate (ZoladexImplant®); goserelin acetate (Zoladex®); histrelin acetate (Histrelinimplant®); hydroxyurea (Hydrea®); Ibritumomab Tiuxetan (Zevalin®);idarubicin (Idamycin®); ifosfamide (IFEX®); imatinib mesylate(Gleevec®); interferon alfa 2a (Roferon A®); Interferon alfa-2b (IntronA®); irinotecan (Camptosar®); lenalidomide (Revlimid®); letrozole(Femara®); leucovorin (Wellcovoring, Leucovorin®); Leuprolide Acetate(Eligard®); levamisole (Ergamisol®); lomustine, CCNU (CeeBU®);meclorethamine, nitrogen mustard (Mustargen®); megestrol acetate(Megace®); melphalan, L-PAM (Alkeran®); mercaptopurine, 6-MP(Purinethol®); mesna (Mesnex®); mesna (Mesnex tabs®); methotrexate(Methotrexate®); methoxsalen (Uvadex®); mitomycin C (Mutamycin®);mitotane (Lysodren®); mitoxantrone (Novantrone®); nandrolonephenpropionate (Durabolin-50®); nelarabine (Arranon®); Nofetumomab(Verluma®); Oprelvekin (Neumega®); oxaliplatin (Eloxatin®); paclitaxel(Paxene®); paclitaxel (Taxol®); paclitaxel protein-bound particles(Abraxane®); palifermin (Kepivance®); pamidronate (Aredia®); pegademase(Adagen (Pegademase Bovine)®); pegaspargase (Oncaspar®); Pegfilgrastim(Neulasta®); pemetrexed disodium (Alimta®); pentostatin (Nipent®);pipobroman (Vercyte®); plicamycin, mithramycin (Mithracin®); porfimersodium (Photofrin®); procarbazine (Matulane®); quinacrine (Atabrine®);Rasburicase (Elitek®); Rituximab (Rituxan®); sargramostim (Leukine®);Sargramostim (Prokine®); sorafenib (Nexavar®); streptozocin (Zanosar®);sunitinib maleate (Sutent®); talc (Sclerosol®); tamoxifen (Nolvadex®);temozolomide (Temodar®); teniposide, VM-26 (Vumon®); testolactone(Teslac®); thioguanine, 6-TG (Thioguanine®); thiotepa (Thioplex®);topotecan (Hycamtin®); toremifene (Fareston®); Tositumomab (Bexxar®));Tositumomab/I-131 tositumomab (Bexxar®); Trastuzumab (Herceptin®);tretinoin, ATRA (Vesanoid®); Uracil Mustard (Uracil Mustard Capsules®);valrubicin (Valstar®); vinblastine (Velban®); vincristine (Oncovin®);vinorelbine (Navelbine®); zoledronate (Zometa®) and vorinostat(Zolinza®); a pharmaceutically acceptable salt thereof, and a mixturethereof.

Any one or more of the specific dosages and dosage schedules of thecompounds of the instant invention, may also be applicable to any one ormore of the therapeutic agents to be used in the combination treatment(hereinafter refered to as the “second therapeutic agent”).

Moreover, the specific dosage and dosage schedule of this secondtherapeutic agent can further vary, and the optimal dose, dosingschedule and route of administration will be determined based upon thespecific second therapeutic agent that is being used.

Of course, the route of administration of the compounds of the instantinvention is independent of the route of administration of the secondtherapeutic agent. In an embodiment, the administration for a compoundof the instant invention is oral administration. In another embodiment,the administration for a compound of the instant invention isintravenous administration. Thus, in accordance with these embodiments,a compound of the instant invention is administered orally orintravenously, and the second therapeutic agent can be administeredorally, parenterally, intraperitoneally, intravenously, intraarterially,transdermally, sublingually, intramuscularly, rectally, transbuccally,intranasally, liposomally, via inhalation, vaginally, intraoccularly,via local delivery by catheter or stent, subcutaneously,intraadiposally, intraarticularly, intrathecally, or in a slow releasedosage form.

In addition, a compound of the instant invention and second therapeuticagent may be administered by the same mode of administration, i.e. bothagents administered e.g. orally, by IV. However, it is also within thescope of the present invention to administer a compound of the instantinvention by one mode of administration, e.g. oral, and to administerthe second therapeutic agent by another mode of administration, e.g. IVor any other ones of the administration modes described hereinabove.

The first treatment procedure, administration of a compound of theinstant invention, can take place prior to the second treatmentprocedure, i.e., the second therapeutic agent, after the treatment withthe second therapeutic agent, at the same time as the treatment with thesecond therapeutic agent, or a combination thereof. For example, a totaltreatment period can be decided for a compound of the instant invention.The second therapeutic agent can be administered prior to onset oftreatment with a compound of the instant invention or followingtreatment with a compound of the instant invention. In addition,anti-cancer treatment can be administered during the period ofadministration of a compound of the instant invention but does not needto occur over the entire treatment period of a compound of the instantinvention.

The term “administration” and variants thereof (e.g., “administering” acompound) in reference to a compound of the invention means introducingthe compound or a prodrug of the compound into the system of the animalin need of treatment. When a compound of the invention or prodrugthereof is provided in combination with one or more other active agents(e.g., a cytotoxic agent, etc.), “administration” and its variants areeach understood to include concurrent and sequential introduction of thecompound or prodrug thereof and other agents.

As used herein, the term “composition” is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product which results, directly or indirectly, fromcombination of the specified ingredients in the specified amounts.

The term “therapeutically effective amount” as used herein means thatamount of active compound or pharmaceutical agent that elicits thebiological or medicinal response in a tissue, system, animal or humanthat is being sought by a researcher, veterinarian, medical doctor orother clinician.

The compounds of the instant invention are useful for the treatmentand/or reducing the severity of rheumatoid arthritis.

The compounds of the instant invention are useful for the treatmentand/or reducing the severity of inflammatory bowel disease.

The compounds of the instant invention are useful for the treatmentand/or reducing the severity of cancer.

The compounds of the instant invention are useful for the treatment ofrheumatoid arthritis.

The compounds of the instant invention are useful for the treatment ofinflammatory bowel disease.

The compounds of the instant invention are useful for the treatment ofcancer.

Further included within the scope of the invention is a method fortreating an inflammatory disease which comprises administering to amammal in need thereof a therapeutically effective amount of a compoundof the instant invention.

Further included within the scope of the invention is a method fortreating an inflammatory disease which comprises administering to amammal in need thereof a therapeutically effective amount of a compoundof the instant invention wherein the inflammatory disease is selectedfrom rheumatoid arthritis, inflammatory bowel disease and cancer.

Further included within the scope of the invention is a method oftreating an inflammatory disease which comprises administering atherapeutically effective amount of a compound of the instant inventionin combination with a second therapeutic agent.

Further included within the scope of the invention is a method oftreating an inflammatory disease which comprises administering atherapeutically effective amount of a compound of the instant inventionin combination with a second therapeutic agent, wherein the secondtherapeutic agent is selected from an anti-cancer agent and ananti-inflammatory agent.

Abbreviations used in the description of the chemistry and in theExamples that follow are: CDCl₃ (chloroform-d); DCM (dichloromethane);DMF (N,N-dimethylformamide); DMSO (dimethyl sulfoxide); EtOAc (ethylacetate); EtOH (ethanol); HPLC (high-performance liquid chromatography);LCMS (liquid chromatograph-mass spectrometer); MeOH (methanol); NMR(nuclear magnetic resonance); Pd(dppf)([1,1-bis(diphenylphosphino)ferrocene]palladium); Pd(Ph₃)₄(palladium(0)tetrakis-triphenylphosphine); POCl₃ (phosphorousoxychloride); THF (tetrahydrofuran); TFA (trifluoroacteic acid); BOC(t-butoxycarbonyl); DMAP (4-dimethylaminopyridine); EDC(N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide); HOBT(hydroxybenzotriazole); LC/MS (liquid chromatograph-mass spectrometer);MeCN (acetonitrile); TLC (thin layer chromatography); CD₃OD(methanol-d); TBTU (O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumtetrafluoroborate).

General Synopsis of Reaction Schemes

The following General Reaction Scheme A-I provides useful details forpreparing the instant compounds. The requisite intermediates are in somecases commercially available or can be prepared according to literatureprocedures. The illustrative General Reaction Scheme below, therefore,are not limited by the compounds listed or by any particularsubstituents employed for illustrative purposes. Substituent labeling(i.e. R groups) as shown in the General Reaction Scheme does notnecessarily correlate to that used in the claims and often, for clarity,a single substituent is shown attached to the compound where multiplesubstituents are allowed under the definitions of Formula I-IIIhereinabove.

As illustrated in Scheme A-I, a nitropyrazine A-1 can be alkylated underbasic condtions to generate the corresponding N-alkyl deriviative A-2.The derivative can then be converted to the corresponding amine A-3, inthis case, by hydrogenation. The newly formed amine can then be coupledwith a carboxylic acid, in this case an aryl carboxylic acid to generatean amide such as compound A-4.

The compounds of this invention may be prepared by employing reactionsas shown in the following Reaction Schemes, in addition to otherstandard manipulations that are known in the literature or exemplifiedin the experimental procedures.

Synopsis of Reaction Schemes

The following Reaction schemes provide useful details for preparing theinstant compounds. The requisite intermediates are in some casescommercially available or can be prepared according to literatureprocedures.

As illustrated in the following schemes, a nitropyrazine 1 can bealkylated under basic condtions to generate the corresponding N-methylderivative 2. The derivative can then be converted to the correspondingamine 3, in this case, by hydrogenation. The newly formed amine can thenbe coupled with a carboxylic acid, in this case an aryl carboxylic acidto generate an amide such as compound 5. Alternatively, an aryl bromidesuch as 6 can be cross-coupled to an aryl pinacol bornate ester toprovide a biaryl such as 8. The biaryl can then be alkylated on theamine to give an N-alkyl derivative such as 10. The ester can behydrolyzed to the acid, in this case using sodium hydroxide. The acidcan then be coupled to an amine as described for compound 5. Removal ofprotecting groups, in this case the tert-butoxylcarbonyl from the aminewill give the desired compounds. Additionally, relevant compounds can bemade by derivitizing intermediates such as 5, in one example by reactionwith pyrrole to provide Example 2.

Determination of IRAK4 Kinase Activity

The kinase activity of IRAK4 is determined by its ability to catalyzethe phosphorylation of a fluorescent polypeptide substrate. The extentof phosphorylation is measured using IMAP technology (Molecular Devices)where the phosphorylated fluorescent substrate binds to the largeM(III)-based nanoparticles which reduces the rotational speed of thesubstrate and thus increases its fluorescent polarization (FP).

Specific compounds of the instant invention were tested in the assaydescribed above and were found to have IC₅₀ values of ≦20 μM againstsubstrate.

Procedure: A 20 μl reaction mixture contains 10 mM TriHCl, pH 7.2, 0.5nM GST tagged IRAK4 (SignalChem), 100 nM fluorescent peptide substrate(RP7030, Molecular Devices), 100 μM ATP, 1 mM DTT, 1 mM MgCl₂, and 0.01%Tween 20. The reaction is initiated by the addition of ATP. Afterincubation for 30 minutes at 25° C., 60 μl of Progressive IMAP Reagent(Molecular Devices) is added to stop the reaction. Change in RP7030's FPis determined by a FP reader (Analyst HT, LJL BioSystems).

Synthesis of Intermediates

LCMS Conditions: Agilent SBC (3.0×50 mm), solvent A: H₂0-0.1% TFA;solvent B: MeCN-0.1% TFA; GRADIENT TABLE: 0 min: 10% B, 0.3 min: 10% B,1.5 min: 95% B, 2.70 min: 95% B, 2.76 min: 10% B, stop time 3.60 min.

In a round bottomed flask, 4-nitro-1H-pyrazole-3-carboxamide (10 g, 63.7mmol), potassium carbonate (26.4 g, 191 mmol) and methyl iodide (15.92mL, 255 mmol) were combined in 200 mL dry N,N-dimethylformamide andstirred 18 hours at room temperature. The reaction mixture was thenconcentrated, diluted with ethyl acetate, washed with water and brine,dried over sodium sulfate and concentrated. The crude mixture waspurified by column chromatography in 25% ethyl acetate in hexanes toyield 2.37 g (12.8 mmol, 20%) of4-nitro-1-methyl-1H-pyrazole-3-carboxamide. 3.66 g (19.76 mmol, 31%) ofregioisomer 1-methyl-4-nitro-1H-pyrazole-5-carboxamide was alsoobtained. LCMS 0.38 min, M/Z=171 [M+H].

In a PARR reaction vessel, 1-methyl-4-nitro-1H-pyrazole-3-carboxamide(2.37 g, 12.8 mmol) was dissolved in ethanol. 10% Palladium on carbon(0.681 g, 0.640 mmol) was added, the vessel was pressurized (40 psi)with hydrogen and the mixture was shaken for 5 hours. The mixture wasfiltered through celite and concentrated to obtain 1.82 g (11.7 mmol,92%) of 4-amino-1-methyl-1H-pyrazole-3-carboxamide. ¹H NMR (DMSO-d6)7.13 (br s, 1H), 7.10 (s, 1H), 6.92 (br s, 1H), 4.61 (s, 2H), 3.70 (s,3H); LCMS 0.27 min, M/Z=141 [M+H].

In a round bottomed flask was combined 0.178 mL (1.28 mmol) oftriethylamine, 131 mg (0.853 mmol) of 1H-benzo[d][1,2,3]triazol-1-olhydrate, 84 mg (0.597 mmol) of4-amino-1-methyl-1H-pyrazole-3-carboxamide and 86.2 mg (0.427 mmol) of6-bromopicolinic acid in 2 mL of dry N,N-dimethylformamide at roomtemperature. The mixture was stirred for ten minutes at roomtemperature, then added 164 mg (0.853 mmol)N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diaminehydrochloride and the reaction mixture was stirred for 5 hours. Themixture was diluted with ethyl acetate, washed with water and brine,dried over sodium sulfate and concentrated to obtain 118 mg (0.362 mmol)of crude 6-bromo-N-(3-carbamoyl-1-methyl-1H-pyrazol-4-yl)picolinamide.LCMS 1.27 min, M/Z=324 [M+H].

In a microwave vial,tert-butyl(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)carbamate(326 mg, 1.02 mmol), methyl 6-bromopicolinate (200 mg, 0.926 mmol),potassium carbonate (1.85 mL, 1.85 mmol) and1,1′-bis(diphenylphosphino)ferrocene dichloro palladium(II)dichloromethane complex (67.7 mg, 0.093 mmol) were combined in 6 mL ofdry tetrahydrofuran, degassed for ten minutes, then sealed and heated to70° C. for 3 hours. The reaction mixture was cooled to room temperature,diluted with ethyl acetate, washed with water and brine, dried oversodium sulfate and concentrated. The crude mixture was then purified viacolumn chromatography in a 0-45% ethyl acetate in hexanes gradient toyield 183 mg (0.556 mmol, 60%) of the product, methyl2′-((tert-butoxycarbonyl)amino)-[2,4′-bipyridine]-6-carboxylate. LCMS2.00 min, M/Z=330 [M+H].

In a round bottomed flask methyl2′-((tert-butoxycarbonyl)amino)-[2,4′-bipyridine]-6-carboxylate (183 mg,0.557 mmol), (bromomethyl)cyclopropane (0.107 mL, 1.11 mmol) and cesiumcarbonate (544 mg, 1.671 mmol) were combined in 1 mL of dryN,N-dimethylformamide and heated to 70° C. for 18 hours. After coolingto room temperature the mixture was diluted with ethyl acetate, washedwith water and brine, dried over sodium sulfate and concentrated. Thecrude mixture was purified by column chromatography in 0-30% ethylacetate in hexanes to give 87.3 mg (0.227 mmol, 40%) of the product,methyl2′-((tert-butoxycarbonyl)(cyclopropylmethyl)amino)-[2,4′-bipyridine]-6-carboxylate.LCMS 2.57 min, M/Z=384 [M+H].

In a round bottomed flask 70 mg (0.213 mmol) methyl2′-((tert-butoxycarbonyl)amino)-[2,4′-bipyridine]-6-carboxylate wasdissolved in 2 mL dry N,N-dimethylformamide and cooled to 0° C. 12.8 mg(0.319 mmol) of sodium hydride was added and the reaction mixture wasstirred for five minutes. 2,2,2-Trifluoroethyl trifluoromethanesulfonate(0.092 mL, 0.638 mmol) was then added and the reaction was stirred andallowed to warm slowly to room temperature overnight. The reaction wasquenched with sodium bicarbonate solution, diluted with ethyl acetate,washed with water and brine, dried over sodium sulfate and concentrated.41.8 mg (0.101 mmol) of crude methyl2′-((tert-butoxycarbonyl)(2,2,2-trifluoroethyl)amino)-[2,4′-bipyridine]-6-carboxylatewas obtained. LCMS 1.91 min, M/Z=412 [M+H].

In a round bottomed flask, methyl2′-((tert-butoxycarbonyl)(cyclopropylmethyl)amino)-[2,4′-bipyridine]-6-carboxylate(200 mg, 0.522 mmol) was dissolved in 4 mL of methanol. A 1 M sodiumhydroxide solution was added (0.574 mL, 0.574 mmol) and the reactionmixture was heated to 50° C. for 3.5 h. The reaction was cooled to roomtemperature and concentrated. The crude reaction mixture was dissolvedin water and 1 M hydrochloric acid was added. The mixture wasconcentrated to obtain 127 mg (0.343 mmol) of crude2′-((tert-butoxycarbonyl)(cyclopropylmethyl)amino)-[2,4′-bipyridine]-6-carboxylicacid that was used without further purification. LCMS 2.32 min, M/Z=370[M+H].

4-Amino-1-methyl-1H-pyrazole-3-carboxamide (71.0 mg, 0.507 mmol),2′-((tert-butoxycarbonyl)(cyclopropylmethyl)amino)-[2,4′-bipyridine]-6-carboxylicacid (144 mg, 0.390 mmol) and HOBt (119 mg, 0.780 mmol) were dissolvedin DMF (2.5 ml). Et₃N (0.163 ml, 1.17 mmol) was added followed by EDC(149 mg, 0.780 mmol) and the reaction was stirred at room temperaturefor 18 h. The mixture was diluted with EtOAc and washed with water andbrine, dried (MgSO₄), filtered and concentrated. The residue waspurified by preparative TLC on silica gel, eluting with CH₂Cl₂/MeOH/NH₃to give tert-butyl(6-((3-carbamoyl-1-methyl-1H-pyrazol-4-yl)carbamoyl)-[2,4′-bipyridin]-2′-yl)(cyclopropylmethyl)carbamate(125 mg, 0.254 mmol, 65% yield) as a white solid.

¹H NMR (DMSO-d6) 8.52 (m, 1H), 8.42 (s, 1H), 8.36-8.31 (m, 2H),8.25-8.15 (m, 3H). 7.74 (s, 1H), 7.56 (s, 1H), 3.93 (s, 3H), 3.83 (d,J=6.8 Hz, 2H), 1.45 (s, 9H), 1.17 (m, 1H), 0.41-0.36 (m, 2H), 0.22-0.19(m, 2H); LCMS 2.37 min, M/Z=492 [M+H].

In a round bottomed flask, 81.1 mg (0.165 mmol) oftert-butyl(6-((3-carbamoyl-1-methyl-1H-pyrazol-4-yl)carbamoyl)-[2,4′-bipyridin]-2′-yl)(cyclopropylmethyl)carbamatewas dissolved in 3 mL of trifluoroacetic acid and stirred at roomtemperature for 7 hours. The reaction mixture was concentrated to yield82.5 mg (0.211 mmol) ofN-(3-carbamoyl-1-methyl-1H-pyrazol-4-yl)-2′-((cyclopropylmethyl)amino)-[2,4′-bipyridine]-6-carboxamide(Example 1).

6-Bromo-N-(3-carbamoyl-1-methyl-1H-pyrazol-4-yl)picolinamide (70 mg,0.216 mmol), pyrrole (0.015 mL, 0.216 mmol) and potassium carbonate (90mg, 0.648 mmol) were dissolved in N,N-dimethylformamide. The vessel wassealed and heated to 120° C. for 2 days. The mixture was diluted withethyl acetate, washed with water and brine and concentrated. The residuewas purified via preparative TLC in 50% ethyl acetate in hexanes to givethe product,N-(3-carbamoyl-1-methyl-1H-pyrazol-4-yl)-6-(1H-pyrrol-1-yl)picolinamide(Example 2).

The following examples were synthesized according to the representativeprocedures stated above:

MS m/z & HPLC IRAK4 IC₅₀ retention Example Structure (nM) time NMR 1

74 392 [M + H]+, 1.8 min 400 MHz (DMSO-d6) 8.42 (s, 1H), 8.39 (br s,1H), 8.31-8.26 (m, 2H), 8.07 (d, 1H), 7.84 (s, 1H), 7.76 (d, 1H), 7.47(s, 1H), 3.94 (s, 3H), 1.16 (m, 1H), 0.56-0.51 (m, 2H), 0.34-0.32 (m,2H) 2

649 311 [M + H]+, 1.8 min 400 MHz (CD₃OD) 11.70 (s, 1H), 8.33 (d, 1H),8.16 (m, 1H), 7.60-7.95 (m, 3H), m 7.35 (d, 1H), 6.84 (d, 1H), 3.96 (s,3H) 3

184 491 [M + H]+, 2.3 min 400 MHz (DMSO-d6) 10.83 (s, 1H) 8.34 (s, 1H),8.17 (s, 1H), 7.97- 8.03 (M, 2H), 7.82 (s, 1H), 7.76 (t, 1H), 7.56 (s,1H), 7.32 (s, 1H), 7.20 (d, 1H), 3.92 (s, 3H), 3.25 (s, 2H), 1.13 (m,1H), 5.55 (m, 2H), 0.30 (m, 2H) 4

785 438 [M + H]+, 1.9 min 400 MHz (DMSO-d6) 8.44 (d, 1H), 8.42 (s, 1H),8.38 (d, 1H), 8.23- 8.19 (m, 3H), 8.06 (m, 1H). 7.74 (s, 1H), 7.59 (s,1H), 3.90 (s, 3H), 1.49 (s, 9H) 5

1447 392 [M + H]+, 1.9 min 400 MHz (DMSO-d6) 10.94 (s, 1H), 8.89 (d,1H), 8.36 (s, 1H), 8.19 (s, 1H), 8.09 (d, 1H), 7.85 (s, 1H), 7.75-7.76(m, 1H), 7.62 (s, 1H), 7.24 (s, 1H), 7.09-7.11 (m, 1H), 6.80 (m, 1H),3.93 (s, 3H), 3.17 (t, 2H), 1.06 (m, 1H), 0.41-0.44 (m, 2H), 0.19-0.21(m, 2H) 6

101 338 [M + H]+, 1.5 min 400 MHz (DMSO-d6) 8.42 (s, 1H), 8.32-8.26 (m,3H), 8.17 (br s, 1H), 8.11 (m, 1H), 8.09-7.77 (m, 3H), 7.56 (s, 1H),3.94 (s, 3H) 7

1099 392 [M + H]+, 1.8 min 400 MHz (DMSO-d6) 10.85 (s, 1H), 9.13 (d,2H), 8.49 (s, 1H), 8.34 (s, 1H), 8.04-8.06 (m, 1H), 7.84 (m, 1H), 7.57(s, 1H), 7.38 (m, 1H), 7.27 (m, 1H), 3.91 (s, 3H), 3.26 (m, 2H), 1.14(m, 1H), 0.52 (m, 2H), 0.28 (m, 2H) 8

2725 392 [M + H]+, 1.7 min 400 MHz (DMSO-d6) 11.19 (s, 1H), 8.13-8.19(m, 2H), 8.10 (d, 1H), 8.07 (s, 1H), 7.91 (s, 1H), 7.40 (d, 1H), 7.26(s, 1H), 4.03 (s, 3H), 3.21 (m, 2H), 1.08 (m, 1H), 0.43 (m, 2H), 0.23(m, 2H) 9

3218 331 [M + H]+, 2.0 min 400 MHz (DMSO- d6) 11.64 (s, 1H), 8.34 (s,1H), 7.75 (t, 1H), 7.65 (m, 1H), 7.53 (m, 1H), 7.40 (m, 1H), 7.09 (m,1H), 3.89 (s, 2H), 3.71 (m, 4H), 3.61 (m, 4H) 10

3452 330 [M + H]+, 1.3 min 400 MHz (DMSO-d6) 11.70 (s, 1H), 9.10 (s,1H), 8.85 (s, 1H), 8.34 (s, 1H), 8.02 (s, 1H), 7.81-7.83 (m, 1H), 7.73(s, 1H), 7.46 (s, 1H), 7.20 (d, 1H), 3.90 (s, 3H), 3.55 (m, 1H), 3.28(s, 2H), 3.20 (s, 2H), 3.12 (s, 2H), 3.04 (s, 2H) 11

1895 323 [M + H]+, 1.4 min 400 MHz (DMSO-d6) 12.01 (s, 1H), 8.74 (d,1H), 8.45 (d, 1H), 3.42 (s, 2H), 8.18-8.25 (m, 2H), 7.75 (s, 1H), 7.65(s, 1H), 3.93 (s, 3H) 12

212 323 [M + H]+, 1.4 min 400 MHz (DMSO-d6) 12.03 (s, 1H), 9.55 (s, 1H),8.70 (d, 2H), 8.38 (m, 2H), 8.13-8.21 (m, 2H), 7.75 (s, 1H), 7.64 (s,1H), 7.54 (m, 1H), 3.93 (s, 3H) 13

637 352 [M + H]+, 1.0 min 400 MHz (DMSO-d6) 11.97 (s, 1H), 8.41 (m, 1H),8.26 (d, 1H), 8.03- 8.18 (m, 1H), 7.94 (s, 1H), 7.86 (d, 1H), 7.72 (d,1H)., 7.50 (s, 1H), 7.41 (t, 1H), 7.04 (d, 1H), 3.93 (s, 6H) 14

3631 332 [M + H]+, 2.2 min 400 MHz (DMSO-d6) 11.96 (s, 1H), 8.06-8.42(m, 5H), 7.49-7.60 (m, 5H), 3.93 (s, 3H) 15

187 396 [M + H]+, 0.7 min 400 MHz (CD₃OD) 11.83 (s, 1H), 8.19- 8.38, (m,3H), 7.98 (m, 2H), 7.72 (d, 1H), 4.00 (s, 3H), 3.98 (s, 3H), 3.92 (s,2H), 3.73 (m, 2H) 16

196 402 [M + H]+, 1.7 min 400 MHz (CD₃OD) 11.89 (s, 1H), 8.39 (s, 1H),8.08-8.15 (m, 3H), 7.68 (m, 1H), 7.61 (m, 1H), 7.44 (d, 1H), 5.88- 6.09,(m, 1H), 4.20 (d, 2H), 3.99 (s, 3H) 17

477 436 [M + H]+, 1.7 min 400 MHz (CD₃OD) 11.81 (s, 1H), 8.20-8.40 (m,3H), 7.90-8.01 (m, 2H), 7.75 (d, 1H), 4.01 (m, 2H), 4.00 (s, 3H),3.40-3.56 (m, 4H), 2.00-2.10 (m, 1H), 1.81 (m, 2H), 1.40-1.50 (m, 2H) 18

127 420 [M + H]+, 1.8 min 400 MHz (CD₃OD) 11.89 (s, 1H), 8.39 (s, 1H),8.08-8.23 (m, 3H), 7.61 (s, 1H), 7.48 (d, 1H), 3.99 (s, 3H), 3.34 (m,2H) 19

283 393 [M + H]+, 1.8 min 400 MHz (CD₃OD) 11.82 (s, 1H), 9.23 (d, 1H),8.4 (s, 1H), 8.21 (m, 2H), 7.98 (q, 3H), 4.00 (s, 3H), 3.36 (m, 2H),1.22 (m, 1H), 0.73 (q, 2H), 0.41 (m, 2H)

General Procedure:6-Bromo-N-(3-carbamoyl-1-methyl-1H-pyrazol-4-yl)picolinamide, (1 equiv),boronic acid (1.1 equiv) and Pd(dppf)Cl₂ are combined in a flask andK₂CO₃ (2 equiv, 1M in water) and THF (0.05 M) are added. The mixture isdegassed and heated to reflux for 6 h. The reaction mixture is cooled toroom temperature and purified by reverse phase HPLC.

Analytical HPLC conditions: The mobile phase (H₂O/acetonitrile) contains0.1% NH₃ and the gradients run from 5% to 100% acetonitrile, hold for0.4 min, then go back to initial condition of 5% acetonitrile. Total runtime is 2 min for each sample.

Time (min) Flow (ml/min) H₂O % Acetonitrile % 0 1 95 5 1.4 1 0 100 1.8 10 100 2.0 1 95 5

The following compounds were thus obtained:

IRAK4 IC₅₀ MS m/z & Example Structure (nM) HPLC retention time 20

2134 352 [M + H]+, 0.82 min 21

2257 405 [M + H]+, 1.01 min 22

362 327 [M + H]+, 0.82 min 23

1105 407 [M + H]+, 0.79 min 24

201 378 [M + H]+, 0.74 min 25

32 325 [M + H]+, 0.66 min 26

1299 375 [M + H]+, 0.62 min 27

134 327 [M + H]+, 0.74 min 28

94 362 [M + H]+, 0.85 min 29

91 356 [M + H]+, 0.79 min 30

426 327 [M + H]+, 0.71 min 31

620 356 [M + H]+, 0.75 min 32

82 354 [M + H]+, 0.63 min 33

739 341 [M + H]+, 0.69 min

Procedure for Synthesis of Amides:

Step 1: A 1 dram vial was charged with4-(2′-((tert-butoxycarbonyl)(cyclopropylmethyl)amino)-[2,4′-bipyridine]-6-carboxamido)-1-methyl-1H-pyrazole-3-carboxylicacid (10 mg, 0.020 mmol), the amine (1.3 eq., 0.026 mmol), TBTU (1.5eq., 9.78 mg, 0.030 mmol) and a solution of CH₂Cl₂ (125 DMF (10 μL) andDIPEA (3 eq., 10.6 μL, 0.061 mmol). The reaction mixtures were shakenovernight. The reaction was checked with LC/MS. In most reactions, themajor peak was the desired product. However, in the case ofpyrimidin-5-amine, the reaction was not complete, so 5 mg of NaH wasadded to the reaction mixture, then it was shaken for 2 more hours, andthe reaction was complete. The reaction mixtures were carried to thenext step without further purification.

Step 2: To the above reaction mixture, was added a solution of CH₂Cl₂(200 μL) and TFA (200 μL, 2.60 mmol). The mixture was shaken for 3 h.LC/MS demonstrated the reaction was complete. Volatiles were removedwith a GeneVac. 0.45 mL DMSO was added to dissolve the mixture. Themixture was filtered and then purified using mass directed reverse phaseHPLC.

MS m/z & HPLC IRAK4 IC₅₀ retention Example Structure (nM) time 34

729 489 [M + H]+, 1.07 min 35

1062 489 [M + H]+, 1.10 min 36

1543 472 [M + H]+, 0.85 min 37

2187 505 [M + H]+, 1.20 min ) 38

4971 497 [M + H]+, 1.01 min 39

2914 475 [M + H]+, 0.98 min 40

535 477 [M + H]+, 1.05 min 41

1829 476 [M + H]+, 0.99 min 42

190 461 [M + H]+, 0.90 min 43

1581 470 [M + H]+, 0.93 min 44

2673 498 [M + H]+, 0.95 min 45

3616 524 [M + H]+, 0.90 min 46

186 505 [M + H]+, 0.88 min 47

4381 484 [M + H]+, 0.90 min 48

2428 490 [M + H]+, 0.89 min 49

260 503 [M + H]+, 1.07 min 50

2677 486 [M + H]+, 0.97 min 51

2285 462 [M + H]+, 0.96 min

What is claimed is:
 1. A compound of Formula III:

wherein: X is CH; a is 0 or 1; b is 0 or 1 m is 0, 1 or 2; R₁ isselected from: H, oxo, (C═O)_(a)O_(b)(C₁-C₁₀)alkyl, (C═O)_(a)O_(b)-aryl,(C═O)_(a)O_(b)(C₂-C₁₀)alkenyl, (C═O)_(a)O_(b)(C₂-C₁₀)alkynyl, CO₂H,halo, OH, O_(b)(C₁-C₆)perfluoroalkyl, (C═O)_(a)NR₅R₆, CN,(C═O)_(a)O_(b)(C₃-C₈)cycloalkyl, S(O)_(m)NR₅R₆, SH, andS(O)_(m)-(C₁-C₁₀)alkyl, said alkyl, aryl, alkenyl, alkynyl, andcycloalkyl are optionally substituted with one or more substituentsselected from R_(a); R₅ and R₆ are independently selected from: H,(C═O)_(a)O_(b)(C_(a)-C₁₀)alkyl, (C═O)_(a)O_(b)-aryl,(C═O)_(a)O_(b)(C₂-C₁₀)alkenyl, (C═O)_(a)O_(b)(C₂-C₁₀)alkynyl, CO₂H,O_(b)(C₁-C₆)perfluoroalkyl, (C═O)_(a)N(R_(a))₂, CN,(C═O)_(a)O_(b)(C₃-C₈)cycloalkyl, S(O)_(m)N(R_(a))₂, SH, andS(O)_(m)-(C₁-C₁₀)alkyl, said alkyl, aryl, alkenyl, alkynyl, andcycloalkyl are optionally substituted with one or more substituentsselected from R_(a); R_(a) is independently selected from R_(b), OH,(C₁-C₆)alkoxy, halogen, cyclopropyl, CO₂H, CN,O_(a)(C═O)_(b)(C₁-C₆)alkyl, oxo, and N(R_(b))₂; and R_(b) isindependently selected from H and (C₁-C₆)alkyl; or a pharmaceuticallyacceptable salt or a stereoisomer thereof.
 2. A compound which isselected from:N-(3-carbamoyl-1-methyl-1H-pyrazol-4-yl)-2′-((cyclopropylmethyl)amino)-[2,4′-bipyridine]-6-carboxamide;tert-butyl(6-((3-carbamoyl-1-methyl-1H-pyrazol-4-yl)carbamoyl)[2,4′-bipyridin]-2′-yl)carbamate;2′-amino-N-(3-carbamoyl-1-methyl-1H-pyrazol-4-yl)[2,4′-bipyridine]-6-carboxamide;N-(3-carbamoyl-1-methyl-1H-pyrazol-4-yl)-2,4′-bipyridine-6-carboxamide;N-(3-carbamoyl-1-methyl-1H-pyrazol-4-yl)-2′-((2-methoxyethyl)amino)-[2,4′-bipyridine]-6-carboxamide;N-(3-carbamoyl-1-methyl-1H-pyrazol-4-yl)-2′-((2,2-difluoroethyl)amino)-[2,4′-bipyridine]-6-carboxamide;andN-(3-carbamoyl-1-methyl-1H-pyrazol-4-yl)-2′-((2,2,2-trifluoroethyl)amino)-[2,4′-bipyridine]-6-carboxamide;or a pharmaceutically acceptable salt or stereoisomer thereof.
 3. Apharmaceutical composition comprising a pharmaceutical carrier, anddispersed therein, a therapeutically effective amount of a compound ofclaim 1.